Evaluating the Response to Two Antiretroviral Medication Regimens in HIV-Infected Pregnant Women, Who Begin Antiretroviral Therapy Between 20 and 36 Weeks of Pregnancy, for the Prevention of Mother-to-Child Transmission

HIV-infected pregnant women who begin taking antiretroviral (ARV) medications in the late stages of pregnancy need an effective medication regimen to reduce the risk of transmitting HIV to their children. This study will examine the virologic response, safety, and tolerability of two different ARV medication regimens in HIV-infected pregnant women who are between 20 and 36 weeks pregnant when they enter the study.

A Phase IV Randomized Trial to Evaluate the Virologic Response and Pharmacokinetics of Two Different Potent Regimens in HIV Infected Women Initiating Triple Antiretroviral Regimens Between 20 and 36 Weeks of Pregnancy for the Prevention of Mother-to-Child Transmission: NICHD P1081

If there is no viral load measurement at the delivery visit, viral load less than 200 copies/mL within 3 weeks prior to delivery.

Number of participants who discontinue efavirenz or raltegravir (whichever was assigned) prior to labor and delivery for any reason (including loss to follow-up) [ Time Frame: Measured up to participants' delivery visit (approximately 36 to 40 weeks) ]

Maternal adverse events of greater than or equal to Grade 3 as defined in the Division of AIDS (DAIDS) toxicity table [ Time Frame: Measured through participants' last study visit 24 weeks after giving birth ]

Infant adverse events of greater than or equal to Grade 3 as defined in the DAIDS toxicity table [ Time Frame: Measured through infants' last study visit at Week 24 ]

Secondary Outcome Measures:

Virologic suppression to below the lower limit of quantification of the assay [ Time Frame: Measured at delivery (approximately 36 to 40 weeks) ]

Number of participants with 1) successful viral load (plasma HIV-1 RNA VL) decrease from entry to Week 2 and VL less than 1,000 copies/ml at all time points after 4 weeks on study drugs, until delivery; and 2) who remain on the assigned study regimen [ Time Frame: Measured through delivery (approximately 36 to 40 weeks) ]

Log10 change in viral load from entry (or screening, if there is no entry viral load) to each time point prior to delivery [ Time Frame: Measured through participants' study visit at delivery (approximately 36 to 40 weeks) ]

Number of participants who experience a stillbirth/fetal demise [ Time Frame: Measured through participants' last study visit at delivery (approximately 36 to 40 weeks) ]

Number of participants who experience a premature birth (less than 34 or less than 37 weeks gestation) [ Time Frame: Measured through participants' last study visit at delivery (approximately 36 to 40 weeks) ]

Number of infants with a low birth weight (less than 1500 or less than 2500 grams) [ Time Frame: Measured through participants' last study visit at delivery (approximately 36 to 40 weeks) ]

Incidence of drug resistance in HIV-infected infants [ Time Frame: Measured through infants' last study visit at Week 24 ]

HIV-1 drug resistance mutations at screening, at 2-4 weeks postpartum in women who have stopped antiretroviral therapy, and at the time of inadequate virologic response (defined in the protocol) using standard and ultrasensitive genotyping methods [ Time Frame: Measured through participants' last study visit 24 weeks after giving birth ]

* Participants may receive a locally supplied nucleoside reverse transcriptase inhibitor (NRTI) backbone in place of lamivudine/zidovudine with permission of the protocol team obtained prior to randomization.

* Participants may receive a locally supplied nucleoside reverse transcriptase inhibitor (NRTI) backbone in place of lamivudine/zidovudine with permission of the protocol team obtained prior to randomization.

While there are many ARV medications and combination regimens available to treat HIV-infected people, the number of ARV medications studied in HIV-infected pregnant women for the prevention of mother-to-child transmission remains limited. HIV-infected pregnant women who begin taking ARV medications late in their pregnancies require effective therapy to reduce the risk of transmitting HIV to their children. Currently, there is no data available that compares the effects of non-nucleoside reverse transcriptase inhibitors (NNRTI) and integrase inhibitors (which are two classes of ARV medications) in pregnant women. The purpose of this study is to compare the safety, tolerance, and virologic and pharmacologic responses to two different medication regimens, each including an NNRTI or integrase inhibitor, in pregnant HIV-infected women who begin ARV therapy late in their pregnancies (i.e., a gestational age between 20 and 36 weeks).

Participants in this study will be randomly assigned to one of two arms. Participants in Arm A will receive lamivudine 150 mg/zidovudine 300 mg twice a day and efavirenz 600 mg each night. Participants in Arm B will receive lamivudine 150 mg/zidovudine 300 mg twice a day and raltegravir 400 mg twice a day. All participants will receive their assigned medications from study entry through delivery. Participants will attend study visits at entry and Weeks 1, 2, and 4; and thereafter, every two weeks until labor and delivery. Study visits will include a medical history review, physical examination, questionnaires, blood collection, and a vaginal swab procedure.

While participants are in labor, they will continue to receive their study medications. Some participants may receive additional or alternate medications according to local standard of care/guidelines. Participants will have a physical examination and blood collection. After delivery, some women will continue to receive ARV medications according to the local guidelines. Participants will attend study visits following the delivery at Weeks 2 to 4, 6, 16, and 24, which will include a medical history review, physical examination, and blood collection. One study visit will include a vaginal swab procedure. Some participants may have vaginal specimens stored for future research.

Participants' babies will receive ARV medications as prescribed by the babies' doctors. Study visits for babies will occur at birth; Weeks 2 to 4, 6, 16, and 24. Each study visit will include a medical history review, physical examination, and blood collection. Select visits will include oral and nasopharyngeal swab collection.

Eligibility

Ages Eligible for Study:

16 Years and older (Child, Adult, Senior)

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Naive to antiretroviral therapy (ART) or have received ART with short course zidovudine (maximum of 8 weeks) for prevention of mother-to-child transmission in previous pregnancies

Willing and able to sign informed consent. Participant must be of an age to provide legal informed consent as defined by the country in which the participant resides. If not, the informed consent must be signed by a legal guardian/parent, as per country guidelines.

Documentation of HIV-1 infection defined as positive results from two samples collected at different time points. The same method may be used at both time points. All samples tested must be whole blood, serum, or plasma. Documentation may be abstracted from medical records to satisfy these criteria for infection. More information on this criterion can be found in the protocol.

Viable pregnancy with gestational age of greater than or equal to 20 weeks to less than or equal to 36 weeks based upon menstrual history and/or ultrasound. Note: If menstrual history is unknown or if there is a discrepancy between menstrual history and ultrasound, determination of gestational age should be based upon best available methodology at each site.

Intends to continue pregnancy

Willingness and intent to deliver at the participating clinical site and to be followed for the duration of the study at the site or associated outpatient facility

Willing to comply with the study regimen

Agrees to use two reliable methods of contraception after delivery if randomized to the efavirenz arm and is sexually active. A barrier method of contraception (condoms, diaphragm, or cervical cap) together with another reliable form of contraception must be used for 4 weeks after stopping efavirenz.

HIV genotypic resistance, as defined in the protocol, to efavirenz or raltegravir or to NRTIs that will be included in the ART regimen. Note: A lack of HIV drug resistance test results at the time of enrollment is not exclusionary.

Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements

Any clinically significant diseases (other than HIV infection) or clinically significant findings during the screening medical history or physical examination that, in the investigator's opinion, would compromise the outcome of this study

Vomiting or inability to swallow medications due to an active, pre-existing condition that prevents adequate swallowing and absorption of study medication

Known allergy/sensitivity to any study drugs or their formulations or sulfonamide allergy

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01618305